Neuroactive substance and uses of one such substance

Co-inventeur en collaboration avec le laboratoire UPRES EA MMS (Substances Marines à Activités Biologiques) – Professeur JF Biard de l’Université de Nantes nous avons déposé un brevet. Ce brevet concerne l’utilisation d’une molécule isolée d’un corail comme traceur des canaux calciques dépendants du potentiel à bas seuil d’activation. A ce jour, il s’agit de la première molécule connue pour agir de cette façon. Un brevet français a été déposé tant pour la structure de cette molécule que pour son activité particulière

Optimization of CABRI power transients with the SPARTE code and the URANIE uncertainty platform

International audienceIn a Pressurized Water Reactor (PWR), the rod ejection is a design basis accident for uncontrolled evolution of the nuclear reaction.In case of failure of a rod mechanism, the rod ejection is caused by the pressure differential between the primary loop (155 bar) and the confinement-s enclosure (atmospheric pressure).It leads to a local power transient and a fast fuel temperature increase.The power transient is limited by the reactivity feedbacks before the automatic reactor shutdown.The CABRI experimental pulsed reactor is funded by the French Nuclear Safety and Radioprotection Institute (IRSN) and is operated by CEA at the Cadarache research center.It is designed to study fuel rods behavior under Reactivity Initiated Accident (RIA) conditions.The tested fuel rod is placed at the center of the CABRI core, inside a pressurized water loop reproducing PWR conditions.CABRI is a pool type reactor, made of 1487 UO$_2$ fuel rods and controlled by 6 Hafnium control rods.A specific device allows the fast depressurization of $^3$He contained in 4 transient rods to reproduce control rods ejection conditions.Based on a BEPU approach, we developed a tool, named SPARTE, for CABRI power transients calculation.This tool is based on point kinetics, simplified thermal-hydraulics and thermal-mechanics.It computes the global behavior of the core by the calculation of a mean fuel rod. It includes models of reactivity insertion specific to the CABRI transient rods system, variable kinetics parameters and variable Doppler coefficient.This code is validated on the basis of 66 CABRI start-up power transients realized during the first quarter of 2017. One goal of the SPARTE code is to be used for the prediction of future CABRI power transients.This paper focuses on methods for optimizing a specific CABRI power transient (FWHM $\simeq$ 30 ms, Deposited energy $\simeq$ 130 $MJ$) using the target characteristics of the pulse. The selection of a method may help the experimentalists and the operation team to minimize the number of white- power transients to perform before the final test with the fuel sample. The optimization can lead to different results, that can be ranked according to their projected uncertainties. Different optimization methods are tested and compared in this paper. The Subplex method based on reiterations of the Nelder-Mead algorithm (simplex method) was selected for its high precision. Indeed, the CABRI power transients are not completely reproducible and present some uncertainties linked to the test parameters. This article focuses on the uncertainties propagation in order to identify and select the parameters that minimize the output uncertainties. The results are very satisfactory and lead to several optimized scenarios that will be tested during the next qualification test campaign

From Agent to Active Sense : Was there an Augustinianism-Averroisant?

Peer reviewe

Environmental and Parental Influences on Offspring Health and Growth in Great Tits (Parus major)

PMCID: PMC3728352This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Qualification and characterization of electronics of the fast neutron Hodoscope detectors using neutrons from CABRI core

The study of Reactivity Initiated Accidents (RIA) is important to determine up to which limits nuclear fuels can withstand such accidents without clad failure. The CABRI International Program (CIP), conducted by IRSN under an OECD/NEA agreement, has been launched to perform representative RIA Integral Effect Tests (IET) on real irradiated fuel rods in prototypical Pressurized Water Reactors (PWR) conditions. For this purpose, the CABRI experimental pulse reactor, operated by CEA in Cadarache, France, has been strongly renovated, and equipped with a pressurized water loop. The behavior of the test rod, located in that loop in the center of the driver core, is followed in real time during the power transients thanks to the hodoscope, a unique online fuel motion monitoring system, and one of the major distinctive features of CABRI. The hodoscope measures the fast neutrons emitted by the tested rod during the power pulse with a complete set of 153 Fission Chambers and 153 Proton Recoil Counters. During the CABRI facility renovation, the electronic chain of these detectors has been upgraded. In this paper, the performance of the new system is presented describing gain calibration methodology in order to get maximal Signal/Noise ratio for amplification modules, threshold tuning methodology for the discrimination modules (old and new ones), and linear detectors response limit versus different reactor powers for the whole electronic chain

The CABRI fast neutron Hodoscope: Renovation, qualification program and first results following the experimental reactor restart

The CABRI experimental pulse reactor, located at the Cadarache nuclear research center, southern France, is devoted to the study of Reactivity Initiated Accidents (RIA). For the purpose of the CABRI International Program (CIP), managed and funded by IRSN, in the framework of an OECD/NEA agreement, a huge renovation of the facility has been conducted since 2003. The Cabri Water Loop was then installed to ensure prototypical Pressurized Water Reactor (PWR) conditions for testing irradiated fuel rods. The hodoscope installed in the CABRI reactor is a unique online fuel motion monitoring system, operated by IRSN and dedicated to the measurement of the fast neutrons emitted by the tested rod during the power pulse. It is one of the distinctive features of the CABRI reactor facility, which is operated by CEA. The system is able to determine the fuel motion, if any, with a time resolution of 1 ms and a spatial resolution of 3 mm. The hodoscope equipment has been upgraded as well during the CABRI facility renovation. This paper presents the main outcomes achieved with the hodoscope since October 2015, date of the first criticality of the CABRI reactor in its new Cabri Water Loop configuration. Results obtained during reactor commissioning phase functioning, either in steady-state mode (at low and high power, up to 23 MW) or in transient mode (start-up, possibly beyond 20 GW), are discussed

The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation

Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels

Rad51 and DNA-PKcs are involved in the generation of specific telomere aberrations induced by the quadruplex ligand 360A that impair mitotic cell progression and lead to cell death

Functional telomeres are protected from non-homologous end-joining (NHEJ) and homologous recombination (HR) DNA repair pathways. Replication is a critical period for telomeres because of the requirement for reconstitution of functional protected telomere conformations, a process that involves DNA repair proteins. Using knockdown of DNA-PKcs and Rad51 expression in three different cell lines, we demonstrate the respective involvement of NHEJ and HR in the formation of telomere aberrations induced by the G-quadruplex ligand 360A during or after replication. HR contributed to specific chromatid-type aberrations (telomere losses and doublets) affecting the lagging strand telomeres, whereas DNA-PKcs-dependent NHEJ was responsible for sister telomere fusions as a direct consequence of G-quadruplex formation and/or stabilization induced by 360A on parental telomere G strands. NHEJ and HR activation at telomeres altered mitotic progression in treated cells. In particular, NHEJ-mediated sister telomere fusions were associated with altered metaphase-anaphase transition and anaphase bridges and resulted in cell death during mitosis or early G1. Collectively, these data elucidate specific molecular and cellular mechanisms triggered by telomere targeting by the G-quadruplex ligand 360A, leading to cancer cell death

Novel Anti-Metastatic Action of Cidofovir Mediated by Inhibition of E6/E7, CXCR4 and Rho/ROCK Signaling in HPV+ Tumor Cells

Cervical cancer is frequently associated with HPV infection. The expression of E6 and E7 HPV oncoproteins is a key factor in its carcinogenicity and might also influence its virulence, including metastatic conversion. The cellular mechanisms involved in metastatic spread remain elusive, but pro-adhesive receptors and their ligands, such as SDF-1α and CXCR4 are implicated. In the present study, we assessed the possible relationship between SDF-1α/CXCR4 signaling, E6/E7 status and the metastatic process. We found that SDF-1α stimulated the invasion of E6/E7-positive cancer cell lines (HeLa and TC-1) in Matrigel though CXCR4 and subsequent Rho/ROCK activation. In pulmonary metastatic foci generated by TC-1 cells IV injection a high proportion of cells expressed membrane-associated CXCR4. In both cases models (in vitro and in vivo) cell adhesion and invasion was abrogated by CXCR4 immunological blockade supporting a contribution of SDF-1α/CXCR4 to the metastatic process. E6 and E7 silencing using stable knock-down and the approved anti-viral agent, Cidofovir decreased CXCR4 gene expression as well as both, constitutive and SDF-1α-induced cell invasion. In addition, Cidofovir inhibited lung metastasis (both adhesion and invasion) supporting contribution of E6 and E7 oncoproteins to the metastatic process. Finally, potential signals activated downstream SDF-1α/CXCR4 and involved in lung homing of E6/E7-expressing tumor cells were investigated. The contribution of the Rho/ROCK pathway was suggested by the inhibitory effect triggered by Cidofovir and further confirmed using Y-27632 (a small molecule ROCK inhibitor). These data suggest a novel and highly translatable therapeutic approach to cervix cancer, by inhibition of adhesion and invasion of circulating HPV-positive tumor cells, using Cidofovir and/or ROCK inhibition